Antenatal care guidelines review Public consultation draft 22 May 2017 Contents

57.2

57.3Thyroid dysfunction

There is currently insufficient evidence to support routine testing for thyroid dysfunction. As there is an association between thyroid dysfunction and adverse pregnancy and fetal outcomes, the focus is on identifying and treating women at high risk of the condition.

57.3.1Background

Thyroid dysfunction in pregnancy often results from a pre-existing condition but may arise during pregnancy. Thyroid dysfunction involves either over or under activity of the thyroid gland.

Hyperthyroidism, in which thyroid hormone levels are raised, is most commonly caused by Graves’ disease, an autoimmune disorder (Marx et al 2008) but may also be induced by excessive exposure to iodine (de Benoist et al 2008). Symptoms include weight loss, heat intolerance and hypertension. It is generally diagnosed and treated before conception (Mestman 2004; Marx et al 2008).

Hypothyroidism is a thyroid hormone deficiency, which may be overt (with symptoms including cold sensitivity, fatigue and dry skin) (Le Groot et al 2012), or subclinical with few or no symptoms but abnormal levels of thyroid hormones (Reid et al 2013). It is most commonly caused by endemic iodine deficiency (Lazarus et al 2011). Autoimmune thyroid disease (eg Hashimoto’s disease) is the most common cause when iodine intake is adequate (Reid et al 2013). Detection of thyroid autoantibodies (to thyroid peroxidase or thyroglobulin) confirms the autoimmune origin of hypothyroidism, or in euthyroid women may indicate increased risk of thyroid dysfunction (Reid et al 2013).

Incidence

Thyroid dysfunction is the second most common endocrine condition (after diabetes mellitus) affecting women of reproductive age (Reid et al 2013).

The incidence of hyperthyroidism in pregnancy is in the range of 0.1–0.4% (Le Groot et al 2012).

Studies in relatively iodine-sufficient populations estimate an incidence of 0.3–0.5% for overt hypothyroidism and 3–5% for subclinical hypothyroidism (Le Groot et al 2012). It is likely that incidence would be higher in areas of iodine insufficiency.

The Australian National Health Survey (ABS 2014) found that, in 2011–2012, iodine levels were relatively low among women of childbearing age. Although women aged 16–44 years had sufficient iodine levels overall, around 18% had iodine levels considered moderately deficient (compared to the national average of 13%) and nearly two thirds (62%) had an iodine level below that recommended by WHO for pregnant and breastfeeding women.

The WHO Global Database on Iodine Deficiency identifies moderate iodine deficiency in some African countries (Algeria, Chad, Senegal), Afghanistan, Belarus and Vietnam (de Benoist et al 2008). Urinary iodine levels associated with a high risk of iodine-induced hyperthyroidism or autoimmune thyroid disease were identified in Brazil, Chile, Ecuador, Liberia and Uganda.

Thyroid autoantibodies are present in 5–15% of women of childbearing age (Le Groot et al 2012).

Risks associated with thyroid dysfunction in pregnancy

Overt hypothyroidism and hyperthyroidism are associated with a range of adverse obstetric outcomes (miscarriage, pre-eclampsia, placental abruption, preterm birth and post-partum haemorrhage) and risks to the baby (low birth weight, increased neonatal respiratory distress and decreased cognitive function) (Lazarus 2011; Lazarus et al 2012).

Studies are now focusing on the potential effect of subclinical thyroid dysfunction and autoimmune disease. A systematic review found that subclinical hypothyroidism in pregnancy is associated with pre-eclampsia (OR 1.7; 95%CI 1.1 to 2.6) and perinatal mortality (OR 2.7; 95%CI 1.6 to 4.7) and the presence of maternal thyroid autoantibodies is associated with miscarriage (OR 3.73; 95%CI 1.8 to 7.6) and preterm birth (OR 1.9; 95%CI 1.1 to 3.5) (van den Boogaard et al 2011). A meta-analysis of cohort studies had similar findings for miscarriage (OR 3.90; 95%CI 2.48 to 6.12) (Thangaratinam et al 2011) and another for preterm birth (RR 1.41; 95%CI 1.08 to 1.84) (He et al 2012).

57.3.2Testing for thyroid dysfunction

Summary of the evidence

Routine testing for thyroid dysfunction is not recommended by the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG 2015) or in the United States (ACOG 2015) and is not addressed in the United Kingdom antenatal guidelines (NICE 2015).

Benefits and harms of testing for thyroid dysfunction

More evidence is needed to assess the benefits or harms of different approaches to testing for thyroid dysfunction in pregnancy on maternal, infant and child health outcomes. A recent Cochrane review (Spencer et al 2015) found that:

compared to case finding, universal testing increased diagnosis and subsequent treatment of thyroid dysfunction but there were no clear differences in outcomes reported (pre-eclampsia, preterm birth, miscarriage, fetal or neonatal death)

compared to no testing, universal testing similarly increased diagnosis and subsequent treatment but there was no clear difference in neurosensory disability for the infant as a child (IQ<85 at 3 years) and other outcomes were not reported.

A subsequent RCT reported that the risk of miscarriage (3.1 vs 8.5%, RR 0.36, 95%CI 0.23 to 0.58, p< 0.001) was lower and the risk of caesarean section higher (41.0 vs 33.5%, RR 1.22, 95%CI 1.08 to 1.39, p<0.001) in the testing group than in the control group (Ma et al 2016). The difference in risk of preterm birth did not reach significance (p=0.772).

Recommendation

58.Do not routinely test pregnant women for thyroid dysfunction.

Evidence reviewed 2016 (no change)

Identifying women at high risk of thyroid dysfunction

While this is an evolving area of practice, the American Thyroid Association considers that women with the following are at high risk of thyroid disease (Alexander et al 2017):

history of thyroid dysfunction

symptoms or signs of thyroid dysfunction,

presence of a goiter

known thyroid antibody positivity.

Other risk factors for thyroid disease include (Alexander et al 2017):

age >30 years

history of type 1 diabetes or other autoimmune disorders

history of pregnancy loss, preterm birth or infertility

history of head or neck radiation or prior thyroid surgery

family history of autoimmune thyroid disease or thyroid dysfunction

BMI ≥40 kg/m²

use of amiodarone, lithium, or recent administration of iodinated radiologic contrast

two or more prior pregnancies

residing in area of moderate to severe iodine deficiency.

Assessment of risk factors at the first antenatal visit is recommended (Le Groot et al 2012). However, onset of thyroid dysfunction can occur later in pregnancy (Moleti et al 2009).

Consensus-based recommendation

59.Recommend thyroid testing to pregnant women who are at increased risk of thyroid dysfunction.

Timing of testing

Low-level evidence was inconsistent regarding the timing of testing for thyroid dysfunction. One study found that first trimester testing identifies mainly minor elevations in TSH, which do not predict adverse pregnancy outcomes (Ong et al 2014), while another found that testing in the second and third trimesters was of limited value (Ekinci et al 2015).

Interpreting thyroid function test results

Thyroid function is initially assessed through testing of thyroid-stimulating hormone (TSH), with measurement of serum thyroxine if maternal TSH is either elevated or reduced.

Diagnosis of thyroid dysfunction in pregnancy is complicated by the fact that normal TSH levels differ from the non-pregnant state (Stagnaro-Green 2011). Applying the general laboratory reference range for TSH to pregnant women can result in misclassification of thyroid status (Dashe et al 2005; Stricker et al 2007; Gilbert et al 2008; Lee et al 2009). TSH levels vary with gestational age and between single and twin pregnancies (Dashe et al 2005). Pregnancy-specific reference ranges that take into account gestational age and fetal number (eg Panesaer et al 2001) should therefore be used. A recent Australian study (Ekinci et al 2013) established the following reference ranges.

Table 4.4.1: Reference ranges for thyroid function in pregnancy by trimester

Trimester (wk)	TSH median (2.5^th–97.5^th centile)	Free thyroxine (pmol/L) mean (95%CI)
1 (9–13)	0.77 (0.03–3.05)	10.7 (5.9–15/5)
2 (22–26)	1.17 (0.42–3.36)	8.1 (4.9–11.3)
3 (35–39)	1.35 (0.34–2.83)	7.8 (4.5–11.0)

Effectiveness and safety of treatments

For women with pre-existing thyroid disease, hormone levels are monitored throughout pregnancy and medications adjusted to maintain a euthyroid state. Regular monitoring and adjustment of medication dosage is also needed when thyroid dysfunction is detected during pregnancy.

Economic analysis

A review of the cost implications of routine testing for thyroid dysfunction was undertaken to inform the development of Module II of these Guidelines in 2014 (included in an appendix to the full Guidelines). The review found insufficient clinical evidence to show that treatment reduces adverse obstetrical and neonatal outcomes. Additionally, there were no economic evaluations relevant to Australia to enable an assessment of the impact of a routine testing program for thyroid dysfunction to detect women with hypothyroidism who have not already been diagnosed. Further research is needed before a comprehensive economic analysis can be conducted.

59.1.1Discussing thyroid dysfunction

Discussion to inform a woman’s decision-making about thyroid function testing should take place before testing and include that:

thyroid function can be affected by autoimmune disorders or inadequate or excessive exposure to iodine in the diet

a family history of thyroid dysfunction means that a woman is more likely to be at risk

an under-active or over-active thyroid can cause complications to the pregnancy and risks to the baby

as some symptoms of an over-active thyroid may be part of normal pregnancy (eg heat intolerance) and under-active thyroid may not cause symptoms, it is important to test thyroid function in women who have symptoms or are at high risk of thyroid problems (eg if they have recently arrived from a country with a high prevalence of iodine deficiency)

consultation with a specialist may be necessary if thyroid problems are identified.

59.1.2Practice summary: thyroid dysfunction

When: A woman has symptoms or risk factors for thyroid dysfunction.

Who: Midwife; GP; specialist obstetrician; Aboriginal and Torres Strait Islander Health Practitioner; Aboriginal and Torres Strait Islander Health Worker; multicultural health worker; endocrinologist.

Discuss the reasons for thyroid function testing: Explain that it is important to check a woman’s thyroid hormone levels because of the effects that thyroid problems can have on the pregnancy and the baby.

Use pregnancy specific ranges: If interpreting thyroid function test results, use pregnancy-specific reference ranges that take into account gestational age and fetal number.

Take a holistic approach: While iodine fortification of bread in Australia means that women will likely enter pregnancy with adequate iodine intake, supplementation (150 micrograms a day) is still recommended during pregnancy and breastfeeding. Women who have recently arrived in Australia may have previous exposure to inadequate or excessive iodine, depending on their country of origin.

Document and follow-up: If a woman’s thyroid function is tested, tell her the results and note them in her antenatal record. Also, note whether thyroid dysfunction is newly diagnosed or was previously treated. Have a follow-up system in place to facilitate timely referral and treatment.

59.1.3Resources

De Groot L, Abalovich M, Alexander EK et al (2012) Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 97(8): 2543–65.

NHMRC (2010) NHMRC Public Statement: Iodine Supplementation for Pregnant and Breastfeeding Women. Canberra: National Health and Medical Research Council.

59.1.4References

ABS (2014) 4364.0.55.006 - Australian Health Survey: Biomedical Results for Nutrients, 2011-12. Canberra: Australian Bureau of Statistics. Available at: www.abs.gov.au

ACOG (2015) Practice Bulletin Number 148: Thyroid disease in pregnancy, April 2015. Obstet Gynecol 125: 996–1005.

Alexander EK, Pearce EN, Brent GA et al (2017) 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid 27(3): 315-89.

Dashe JS, Casey BM, Wells CE et al (2005) Thyroid-stimulating hormone in singleton and twin pregnancy: importance of gestational age-specific reference ranges. Obstet Gynecol 106(4): 753–57.

de Benoist B, McLean E, Andersson M et al (2008) Iodine deficiency in 2007: global progress since 2003. Food Nutr Bull 29(3): 195–202.

De Groot L, Abalovich M, Alexander EK et al (2012) Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 97(8): 2543–65.

Ekinci EI, Chiu WL, Lu ZX et al (2015) A longitudinal study of thyroid autoantibodies in pregnancy: the importance of test timing. Clin Endocrinol (Oxf) 82(4): 604-10.

Ekinci EI, Lu ZX, Sikaris K et al (2013) Longitudinal assessment of thyroid function in pregnancy. Ann Clin Biochem 50(Pt 6): 595–602.

Gilbert RM, Hadlow NC, Walsh JP et al (2008) Assessment of thyroid function during pregnancy: first-trimester (weeks 9-13) reference intervals derived from Western Australian women. Med J Aust 189(5): 250–53.

He X, Wang P, Wang Z et al (2012) Thyroid antibodies and risk of preterm delivery: a meta-analysis of prospective cohort studies. Eur J Endocrinol 167(4): 455–64.

Lazarus JH, Bestwick JP, Channon S et al (2012) Antenatal thyroid screening and childhood cognitive function. New Engl J Med 366(6): 493–501.

Lazarus JH (2011) Thyroid function in pregnancy [Review]. Brit Med Bull 97: 137–48.

Lee RH, Spencer CA, Mestman JH et al (2009) Free T4 immunoassays are flawed during pregnancy. Am J Obstet Gynecol 200(3): 260–66.

Ma L, Qi H, Chai X et al (2016) The effects of screening and intervention of subclinical hypothyroidism on pregnancy outcomes: a prospective multicenter single-blind, randomized, controlled study of thyroid function screening test during pregnancy. J Matern Fetal Neonatal Med 29(9): 1391-4.

Marx H, Amin P, Lazarus JH (2008) Hyperthyroidism and pregnancy. BMJ 336: 663–67.

Mestman JH. Hyperthyroidism in pregnancy. Best Pract Res Clin Endocrinol Metab 18 (2): 267–88.

Moleti M, Pio Lo Presti V, Mattina F et al (2009) Gestational thyroid function abnormalities in conditions of mild iodine deficiency: early screening versus continuous monitoring of maternal thyroid status. Eur J Endocrinol 160(4): 611–17.

NICE (2016 update) Antenatal Care for Uncomplicated Pregnancies CG62. London: National Institute for Health and Care Excellence.

Ong GS, Hadlow NC, Brown SJ et al (2014) Does the thyroid-stimulating hormone measured concurrently with first trimester biochemical screening tests predict adverse pregnancy outcomes occurring after 20 weeks gestation? J Clin Endocrinol Metab 99(12): E2668-72.

Panesar NS, Li CY, Rogers MS (2001) Reference intervals for thyroid hormones in pregnant Chinese women. Ann Clin Biochem 38(Pt 4): 329–32.

RANZCOG (2015) Testing for hypothyroidism during pregnancy with serum TSH. C-Obs 46. Melbourne: Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

Reid SM, Middleton P, Cossich MC et al (2013) Interventions for clinical and subclinical hypothyroidism in pregnancy. Cochrane Database Syst Rev Issue 5. Art. No.: CD007752. DOI: 10.1002/14651858.CD007752.pub2.

Spencer L, Bubner T, Bain E et al (2015) Screening and subsequent management for thyroid dysfunction pre-pregnancy and during pregnancy for improving maternal and infant health. Cochrane Database Syst Rev(9): CD011263.

Stagnaro-Green A (2011) Overt hyperthyroidism and hypothyroidism during pregnancy. Clin Obstet Gynecol 54(3): 478–87.

Stricker RT, Echenard M Eberhart R et al (2007) Evaluation of maternal thyroid function during pregnancy: the importance of using gestational age-specific reference intervals. Eur J Endocrinol 157(4): 509–14.

Thangaratinam S, Tan A, Knox E et al (2011) Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ 342: d2616-d2616.

van den Boogaard E, Vissenberg R, Land JA et al (2011) Significance of (sub)clinical thyroid dysfunction and thyroid autoimmunity before conception and in early pregnancy: a systematic review. Human Reprod Update 17(5): 605–19.